Enantioselectivity in the synthesis of 3,5-disubstituted Δ2-isoxazolines

Norman, Amber L.; Mosher, Michael

doi:10.1016/j.tetlet.2008.04.125

Cited by 27 publications

(8 citation statements)

References 11 publications

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“…Optically active 2‐isoxazolines are mostly constructed by the asymmetric 1,3‐dipolar cycloaddition of nitrile oxides to olefins,5a–h the asymmetric cyclization of β,γ‐unsaturated oximes,5i stereoselective ring‐closure reaction through oximes of chiral Michael adducts of thiophenol to chalcones,5j and proline‐catalyzed conjugate addition/oxime‐transfer reactions of unsaturated aldehydes 5k. These methods, however, were not applicable to the synthesis of 1 because of the limitations in substrate specificity, and indeed, the catalytic enantioselective synthesis of trifluoromethyl‐substituted 2‐isoxazolines 1 has not been reported.…”

Section: Methodsmentioning

confidence: 99%

Enantioselective Synthesis of Trifluoromethyl‐Substituted 2‐Isoxazolines: Asymmetric Hydroxylamine/Enone Cascade Reaction

et al. 2010

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Heterocycles containing a trifluoromethyl group are representatives of a major structure type in agricultural and medicinal chemistry, and thus the development of a simple and flexible method to generate a novel trifluoromethylated heterocyclic system has received much attention.[1] Trifluoromethyl-substituted 2-isoxazolines are amongst an important class of heterocyclic compounds with remarkable biological activities, and they make interesting synthetic targets.[2] Since the first discovery of the structurally unique 3,5-diaryl-5-(trifluoromethyl)-2-isoxazoline derivatives 1 (Figure 1) as pest control agents in 2004, [3a] the search for new agrochemicals and veterinary medicines has focused largely on this skeleton, [3] despite their diverse structural variants.[2] Thus far, more than 20 000 compounds have been synthesized and patented in the past 5 years (the results of substructure searching using 1 with Scifinder), and many promising drug candidates have been disclosed including an antiparasiticide compound of either type A or B (Figure 1).[3] More interestingly, recent biological evaluation of the optically active type B compound (X 6 = CONHCH 2 COCH 2 CF 3 ), obtained by HPLC methods using a chiral stationary phase, revealed that the R enantiomer of B is inactive and the S enantiomer is the active component.[3b] Once the importance of the optical purity of these compounds was verified, the next challenge was to control the stereochemistry at a quaternary carbon center bearing a CF 3 group. As part of our ongoing research programs directed to the development of efficient methods for the asymmetric synthesis of organofluorine compounds, [4] we disclose herein the synthesis of trifluoromethyl-substituted 2-isoxazolines by a cinchona alkaloid catalyzed asymmetric hydroxylamine/enone cascade reaction consisting of a conjugate addition/cyclization/dehydration sequence (Scheme 1).Optically active 2-isoxazolines are mostly constructed by the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to olefins, [5a-h] the asymmetric cyclization of b,g-unsaturated oximes, [5i] stereoselective ring-closure reaction through oximes of chiral Michael adducts of thiophenol to chalcones, [5j] and proline-catalyzed conjugate addition/oxime-transfer reactions of unsaturated aldehydes.[5k] These methods, however, were not applicable to the synthesis of 1 because of the limitations in substrate specificity, and indeed, the catalytic enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 1 has not been reported. We therefore started to investigate the asymmetric version of the nonchiral 2-isoxazoline-formation reaction.[3c] We first examined the reaction of (E)-4,4,4-trifluoro-1,3-diphenylbut-2-en-1-one (2 a) with hydroxylamine in the presence of NaOH and a catalytic amount of N-3,5-bis(trifluoromethylbenzyl) quinidinium bromide (3 a) as a chiral phase-transfer catalyst in toluene at À30 8C (Table 1). The trifluoromethylated 2-isoxazoline (R)-1 a was formed in 89 % ee, although the yield was 24 % (Table 1, ...

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Section: Methodsmentioning

confidence: 99%

Enantioselective Synthesis of Trifluoromethyl‐Substituted 2‐Isoxazolines: Asymmetric Hydroxylamine/Enone Cascade Reaction

et al. 2010

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“…[2] The conventional synthesis methods of isoxazolines mainly rely on the 1,3-dipolar cycloaddition of nitrile oxides and olefins, in which certain oxidants are generally required for the initial oxidation of aldoximes to nitrile oxides. [4][5][6][7] Chen et al firstly reported the palladium-catalyzed oxyarylation of β,γ-unsaturated oximes with aryl bromides. Recently, a variation was presented by which a variety of functionalized isoxazolines were regioselectively furnished by the palladium-catalyzed annulation of β,γ-unsaturated oximes.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a variation was presented by which a variety of functionalized isoxazolines were regioselectively furnished by the palladium-catalyzed annulation of β,γ-unsaturated oximes. [5,6] Transition-metal-catalyzed vicinal difunctionalization of unactivated olefins provides a powerful tool for olefin trans-yields. Intramolecular 5-exo-trig ring closure occurred, giving rise to sole regioselectivities.…”

Section: Introductionmentioning

confidence: 99%

“…[4] Later, Mosher et al and Loh et al developed the regioselective methoxycarbonylation and intramolecular dioxygenation of β,γ-unsaturated oximes, respectively. [5,6] Transition-metal-catalyzed vicinal difunctionalization of unactivated olefins provides a powerful tool for olefin trans-yields. To demonstrate the value of the method, the brominated isoxazoline has been further converted to other useful synthetic feedstock.…”

Section: Introductionmentioning

confidence: 99%

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Oxime‐Mediated Oxychlorination and Oxybromination of Unactivated Olefins

et al. 2015

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“…Recently, Kündig and co-workers reported a ruthenium catalyst that appeared to overcome this limitation, but the substrate scope was still very restricted. [4] In addition to cycloadditions, a catalytic asymmetric cyclization of b,g-unsaturated oximes has been reported, [5] but only modest selectivities have been attained with this method so far. Herein, we report a new catalytic enantioselective method to prepare 5-substituted 2-isoxazolines that applies a small organic catalyst as the source of chirality and enables the use of different a,b-unsaturated aldehydes as starting materials.Recently, we disclosed a reaction for the preparation of 3unsubstituted 2-isoxazolines in which aniline salts such as 3 (Scheme 1) catalyzed the condensation of a,b-unsaturated aldehydes and oximes to produce these rare heterocycles.…”

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confidence: 99%